Peripheral neuropathy is a common and clinically significant complication of cancer chemotherapy. Importantly, this neuropathy is a dose-limiting effect of many chemotherapeutic agents. Since the clinical outcome is often related to the tolerated dose, a drug which reduces the neuropathy would increase the tolerated dose and thus increase survival as well as improve quality of life. Observations of both animal and human effects of chemotherapeutic agents suggest that inappropriate triggering of a latent program for cell death in the affected neurons contributes to the pathology. Recent research indicates that this program involves the active production of specific killer proteins rather than being a passive process. This provides the opportunity to interfere with the process by inhibition of the killer function. Programmed cell death can be modeled in vitro and in these same systems chemotherapeutic agents are selectively toxic. This proposal seeks to strengthen the evidence for a connection between programmed cell death and chemotherapy-induced neuropathy and to develop and begin using a screening scheme for the identification of structural leads. In phase II this will be expanded into a synthetic program for drug development.